This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 1 diabetes mellitus (T1DM) is currently managed using modulation of dietary carbohydrates and insulin. Parasoxical post-meal hyperglucagonemia is associated with psot-prandial hyperglycemia in T1DM. Glucagon suppressors such as the amylin analog, pramlintide, and the glucagon like peptide-1 (GLP-1) analog, exenatide, are new agents approved for use in adults with diabetes. We have previously demonstrated pramlintide reduces post-prandial hyperglycemia by decreasing glucagon and delaying gastric emptying in adolescents with T1DM. GLP-1 in animal studies has been shown to increase beta cell mass and decrease apoptosis. Only limited information is available on the use of GLP-1 in T1DM. No studies have been reported to determine if pramlintide and exenatide have similar effects on glycemic control in T1DM. The overall aim of this proposal is to develop safe and effective strategies targeting glucagon and improving glycemic control in T1DM. The overall aim of this proposal is to develop safe and effective strategies targeting glucagon and improving glycemic control in pediatric T1DM. The specific aim of Protocol 1 is to establish a glucose-lowering dose of exenatide in T1DM equivalent to that which we have established for pramlintide. To this end 17 subjects with T1DM will be randomized to 4 studies with varying pramlintide doses. Glucagon suppression and delay in gastric emptying will also be assessed. Higher doses of exenatide will result in more pronounced effects on gastric emptying and glucagon suppression as compared to lower doses. SPECIFIC AIMS To establish an effective dose of exenatide, which will normalize post-prandial hyperglycemia without causing hypoglycemia. To determine the effects of exenatide on gastric emptying and glucagon suppression. The long-term objective of this protocol is to develop a safe exenatide dose that can be used in new onset patients with T1DM. The antiapoptic properties of exenatide will be tested to determine if using exenatide early in the diagnosis prolongs beta cell survival and hence prolonging of the honeymoon period of diabetes.